Subcortical white matter (SCWM) neurons are a common feature in the primate neocortex and are present in large numbers in the human. These cells are believed to be the remnant of the subplate and may have served guidepost functions during neocortical development. The function of SCWM neurons in the adult is unknown, however because they have extensive axonal processes in early postnatal life, they may be able to affect the activity of large regions of cortex into adulthood. Although the significance is not yet known, there are also increased numbers of SCWM neurons in a variety of neurological diseases, including schizophrenia, forms of epilepsy and, perhaps, Alzheimer's disease. It is important, therefore, to examine the synaptic organization and physiology of these cells for a complete understanding of both normal and pathological cortical function. The goal of this project is to test the hypothesis that SCWM neurons are integrated into the neocortical circuitry. This study is uniquely suited to be carried out using human tissue for two reasons; 1) the density of SCWM neurons increases with the complexity of the organism, therefore studies carried out in animals such as rodents or cats may not be applicable to humans; 2) the costs of carrying out such a study in non-human primates would be prohibitive. Tissue from patients undergoing resection for the treatment of intractable epilepsy is routinely available. These resections typically include areas involved in seizure generation as well as relatively normal tissue adjacent to these areas. We will examine whether SCWM neurons are integrated into the neuronal circuitry using a combination of anatomical and physiological techniques. If this hypothesis is valid, there should be evidence for both synaptic inputs and outputs between these cells and the neocortex. Electron microscopic studies of this tissue will be performed to examine whether there are synapses onto the soma and proximal dendrites of these cells that arise from the cortex. In addition, the synaptic output of these cells will be assayed by examining the axonal arbors of biocytin- filled cells. The synaptic targets of SCWM cells will be identified using double labeling studies. Physiological studies will be performed by recording from visually identified SCWM neurons. In addition to characterizing these cells physiologically, we will examine whether these cells receive spontaneous or evoked synaptic activity from the neocortex and the possible transmitter(s) underlying any synaptic activity. All cells studied physiologically will be labeled with biocytin to allow us to verify the cell type and for use in the anatomical experiments. These studies will provide the first information on the possible role of these cells in the function of the adult neocortex. Given the possible involvement of these cells in a variety of neurological disorders, it is critical to characterize these cells completely.